HIV disease progression varies widely among individuals. Although some genetic or HIV protein factors have been identified that affect disease progression, these do not explain slow HIV disease progression in most cases. We and others found an association between infection with GB virus C (GBV-C) infection, a common, nonpathogenic human flavivirus, and prolonged survival in several cohorts of HIV-infected people. GBV-C infection is also associated with decreased maternal-fetal HIV transmission. These epidemiological associations are strengthened by in vitro studies demonstrating that GBV-C infection of CD4 cells potently inhibits HIV replication by modulating host cellular gene expression resulting in decreased HIV entry and facilitating CD4 survival. HIV leads to qualitative and quantitative immune dysfunction. Although HIV directly kills CD4 cells, the number of cells infected with HIV is insufficient to explain the overall CD4 depletion. The precise mechanism(s) by which HIV depletes CD4+ T cells is incompletely understood. Immune activation induced by infection with HIV itself or other microbes (e.g. GI bacteria), appears to be critical for CD4 depletion. Recent data found that GBV-C infection dampens CD4 and CD8 T cell activation in vivo and in vitro, suggesting that GBV-C may influence HIV disease in this manner. In addition, GBV-C infection was associated with a lack of CD4 expansion among people who received recombinant IL-2 therapy (rIL-2) in a blinded, prospective, multicenter trial. Although the study was small and some data were missing, the results were striking. If confirmed in larger cohorts, GBV-C infection would be a critical variable in the interpretation of rIL-2 therapy and potentially other immunomodulatory trials. We hypothesize that GBV-C interacts with IL-2, potentially via the IL-2 receptor to dampen T cell activation and proliferation, resulting in delayed HIV disease progression. To test this hypothesis we propose three aims. First, we will confirm our initial epidemiological findings in a larger cohort (ESPRIT). Secondly, we will examine the effect of GBV-C on changes in T cell activation and proliferation in lymphocytes from HIV-infected and uninfected people in relation to IL-2 activation. Finally, we will characterize the GBV-C protein(s) and protein domains involved in cellular interactions dampening T cell activation in vitro. Understanding factors that delay HIV disease is critical for understanding disease variability in HIV infection, and identification of the mechanisms by which CD4 cells are preserved during HIV infection may be exploited to identify novel approaches of cellular-based HIV therapeutics.